Methods have been developed to systematically assess and plot the longitudinal course of affective illness in relationship to pharmacological interventions and psychosocial stressors. We have characterized a course of illness systematically in this fashion in more than 196 patients with primary affective disorders. These data re-document the early observations that the course is often not only one of recurrences, but of progressive increases in frequency of cycling and severity of illness. Ultra-rapid and ultradian cycling have also been identified. This cycle acceleration is occurring in the context of a decreasing incidence of psychosocial stressors precipitating affective episodes; i.e., as in sensitization and kindling, they are occurring autonomously. It is against this backdrop that pharmacological intervention must be considered. We have noted that one of the previous traditional interventions for bipolar depression, tricyclic antidepressants, appear to carry a 35% risk of causing definite or likely switches into mania. In those individuals who show this induction, we have observed a pattern of increased rapidity of cycling in the year prior to NIMH admission and longer hospital stays at NIMH, suggesting that TCA-induced switches are a marker if not the cause of a more malignant course of illness. A new phenomenon of lithium discontinuation-induced refractoriness has been described that presents an additional rationale for continuing patients on long-term maintenance treatment. We have begun to assess neurobiological correlates of course of illness using a variety of neurotransmitter and endocrine markers as well as proteins in the CSF. In patients studied after a prolonged period of medication-free evaluation, we have observed that rapid cyclers show significantly higher T4 and free T4 levels compared with non-rapid cyclers. These data are contrary to previous notions in medicated patients, where rapid cycling was often associated with hypothyroidism. In bipolar patients, more lethal suicide attempts appear to occur later in the course of illness in contrast with unipolar patients reported in the literature where these often occur after the first episode.